Impetigo, a highly contagious bacterial infection of the superficial layers of the epidermis, is a common childhood disorder but can also be found amongst adults. It is a very common bacterial skin infection and one of the most common skin diseases among children, accounting for about 10% of skin diseases treated in US pediatric clinics. The bacteria held responsible are Staphylococcus aureus and Streptococcus pyogenes, or often a combination of the two. Impetigo is usually transmitted by direct contact but fomites also play an important role. Methicillin-resistant S. aureus (MRSA) is being found with increasing frequency.
Impetigo has three clinical varieties: impetigo contagiosa (common impetigo), bullous impetigo, and ecthyma. Features of all three types of impetigo, however, may coexist in any individual patient.
A number of topical compositions containing pharmaceutically active ingredients are known in the art for the treatment of impetigo. Topical mupirocin 2% (Bactroban ointment and cream) is a treatment option, as are older treatments, such as topical gentian violet and vioform. For many patients, mupirocin is a viable treatment option for MRSA, however, resistance of bacteria to mupirocin has been widely reported. More recent data have shown that topical fusidic acid 2% (Fucidin cream) is useful for impetigo, and is thought to be equally as effective as mupirocin.
Retapamulin 1% (Altabax ointment), recently approved by the FDA, is a drug in the new class of pleuromutilin antibiotics for the topical treatment of impetigo due to Staphylococcus aureus (methicillin-susceptible only) or Streptococcus pyogenes. 
In clinical trials, retapamulin and mupirocin were administered for a whole week, three times a day thus making it burdensome for caregivers of the impetigo patients, who are frequently infants and young children, so a product that requires less applications would be advantageous and could improve patient compliance.
The vehicles for both retapamulin and mupirocin are ointments. Ointments are thick pastes, which are relatively difficult to apply and spread on skin, result in a greasy and sticky appearance, and are usually not appealing for use, especially in facial treatments. Compliance with ointments is usually relatively poor, because when applied they require rubbing onto the infected wound leading to pain and transfer of infectious organisms to other sites. Furthermore, when ointments containing petroleum are applied onto a wound, metabolic products and excreta from the wound cannot be easily removed because of the difficulty of passing through the hydrophobic petroleum barrier. In addition, an active drug ingredient, which is dissolved or dispersed in the petroleum carrier, is likely not efficiently absorbed into the wound tissue, thus, the efficacy of the drug is affected. Another example is ophthalmologic ointments, which are applied into the eye, and make the eye area sticky and uncomfortable. Moreover, in a physiological aspect, petroleum restricts respiration of the wound tissue and disturbs to the normal respiration of the skin.
Therapeutic topical compositions must stay on the skin for a sufficient period of time to allow the active agent to be absorbed onto the skin; to perform its activity; to also remain there in a preventative role; they must not irritate the skin; and they must be perceived by the patient as pharmaceutically convenient in order to achieve sufficient patient compliance. By “pharmaceutically convenient”, it is meant that the skin look and feel to the patient is good, i.e., it must not be too watery or too greasy and it must easily be applied.
Tetracycline antibiotics, such as tetracycline, oxytetracycline, demeclocycline, doxycycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, chlorotetracycline and tigecycline, are extremely unstable compounds and are sensitive to many formulation excipients (for example, water, short chain alcohols, certain polymers, certain hydrophilic solvents and surfactants). Thus, most tetracyclines, e.g., minocycline and doxycycline, currently exist only in solid oral dosage forms or are given by injection or infusion.
Oral antibiotics (e.g., antistaphylococcal penicillins, amoxicillin/clavulanate [Augmentin], cephalosporins, macrolides) are effective for the treatment of impetigo; erythromycin is less effective. (C Cole and J Gazewood, Diagnosis and Treatment of Impetigo Am Fam Physician. 2007 Mar. 15; 75(6):859-864.)
Regardless, a seven-day course of oral antibiotics is usually recommended for symptoms to clear up but they can be associated with a variety of side effects which inter alia may include stomach ache, nausea, vomiting, diarrhea, and the appearance of yeast infections, such as thrush (Candidiasis), a fungal infection of the mucous membranes.
Furthermore, oral tetracycline antibiotics are generally not used in the treatment of impetigo, primarily because they are prohibited for use in young children due to the ability to cause tooth discoloration. Common side effects of oral minocycline include diarrhea, dizziness, drowsiness, indigestion, lightheadedness, loss of appetite, nausea, sore mouth, throat or tongue, and vomiting. Minocycline may also cause severe side effects, including severe allergic reactions, bloody stools, blurred vision, change in the amount of urine produced, fever, chills, sore throat, hearing problems, joint pain, muscle pain or weakness, rectal or genital irritation, red, swollen, blistered, or peeling skin, ringing in the ears, seizures, severe or persistent headache, severe skin reaction to the sun, watery diarrhea, stomach cramps or pain, swollen glands, symptoms of pancreatitis, trouble swallowing, unusual bruising or bleeding, unusual tiredness or weakness, vaginal irritation or discharge, white patches in the mouth and yellowing of the skin or eyes. Due to these side effects, the FDA added oral minocycline in 2009 to its Adverse Event Reporting System (AERS), a list of medications under investigation by the FDA for potential safety issues.
Minocycline has a spectrum of activity and a mode of action similar to that of tetracycline but it is more active against many species including Staphylococcus aureus, streptococci, Neisseria meningitidis, various enterobacteria, Acinetobacter, Bacteroides, Haemophilus, Nocardia, and some mycobacteria, including M. leprae. Partial cross-resistance exists between minocycline and other tetracyclines but some strains resistant to other drugs of the group remain sensitive to minocycline, perhaps because of better cell-wall penetration. Minocycline is a tetracycline derivative with uses similar to those of tetracycline. Minocycline is given orally or by injection or infusion. It is also a component of multidrug regimens for the treatment of leprosy and has been used in the prophylaxis of meningococcal infection to eliminate the carrier state, but the high incidence of vestibular disturbances, presumeably resulting from it being given systemically, means that it is not the drug of choice for the latter. It has neuroprotective properties, it is being investigated for motor neurone disease, and for the management of Huntington's chorea. It is used in the treatment of rheumatoid arthritis and in the prevention or treatment of various skin disorders, including acne.
Due to the broad spectrum of antibacterial activity of tetracycline antibiotics, especially minocycline and doxycycline, topical treatment comprising tetracycline compositions, which can reduce adverse systemic exposure of such antibiotics is warranted.
Novel, stable, patient-friendly topical hydrophobic therapeutic breakable gel and foamable compositions comprising tetracycline, without surfactants, have been described, for example in U.S. application Ser. Nos. 13/499,501, 13/499,727, 13/499,475, and 13/499,709, U.S. Publication No. 2011/0281827, WO11/039,637, WO11/039,638, WO 11/138,678 and WO 2011/064631 all of which are herein incorporated in their entirety by reference.
The instability of minocycline was observed and confirmed in a compatibility study with pharmaceutical excipients described, for example, in WO11/039,637. The study identified and demonstrated different hydrophilic solvents that were incompatible with minocycline and different hydrophobic solvents, emollients and waxes that revealed compatibility with minocycline. Fatty alcohols, as well as some fatty acids (such as stearic acid, oleic acid and palmitic acid) were found to be compatible with minocycline. Additionally, a few certain surfactants (e.g., sucrose fatty esters) and some additives (aerosil and menthol) were disclosed to be compatible with minocycline, whereas other surface active agents including polysorbates, sorbitan esters of fatty acids, polyoxyethylene alkyl ethers and polyoxyethylene esters of fatty acids were found not to be compatible.
It was further discovered, for example, in WO11/039,637 that addition of water caused rapid degradation of minocycline and addition of antioxidants (alpha-tocopherol, BHA/BHT and propyl gallate) did not prevent such degradation. Furthermore, compatible excipients became incompatible in the presence of water and addition of antioxidants did not remedy this result. It was also shown, for example, in WO11/039,637 that minocycline has activity that decreases apoptosis and increases cell viability.
It was further found, for example, in WO11/039,637, in in-vitro skin delivery studies that enhanced penetration was achieved without the need of adding a hydrophilic solvent and thus degradation of minocycline could be further reduced or prevented. Minocycline was found to have been delivered intradermally at sufficient levels to treat skin infections but did not pass through the skin transdermally and therefore topical application should be essentially free from adverse systemic effects.
Wound is an injury to the body (as from violence, accident, or surgery) that typically involves laceration or breaking of a membrane (as the skin) and usually damage to underlying tissues (Merriam Webster Dictionary). Burns are injuries to tissues caused by heat, friction, electricity, radiation, or chemicals. Wounds and burns are often colonized by microbiologic pathogens, including Gram-positive bacteria, such as Staphylococcus aureus and/or Streptococcus pyogenes; and Gram-negative bacteria, e.g., Pseudomonas aeruginosa. 
Despite the very common occurrence of skin infections, only a limited number of topical antibiotics are approved for the treatment of wounds and particularly infected wounds. Mupirocin (Bactroban, GSK) is an antibiotic, developed by GSK. Emerging resistance to mupirocin is becoming a concern. In coagulase-negative staphylococci isolates, mupirocin resistance rates are higher, ranging from 12.7% in Europe to 38.8% in the United States. Retapamulin (Altabax, GSK) is another topical antibiotic used for wound treatment. Fucidin (LEO Pharma) is effective in primary and secondary skin infections caused by sensitive strains of S. aureus, Streptococcus species and C. minutissimum, but is virtually inactive against Gram-negative bacteria.
These three products require 6-10 days of treatment to attain clinical improvement. For example, Altabax attained 85.6% clinical success after 7 days, vs. 52.1% effect of the respective placebo.
Additionally, the above products are available as ointments, which when applied require rubbing onto the lesion, which is frequently an infected wound, leading to pain and transfer of infectious organisms to other sites. An additional drawback of Bactroban and Fucidin is that they require treatment three times daily, which imposes inconvenience to the caregivers of the impetigo patients, who are mostly infants and young children, so a product that requires less applications is advantageous and likely to improve compliance.
Acne, including acne vulgaris and acne-rosacea (also termed “rosacea”) are skin diseases which involve infected lesions, including non-inflammatory and inflammatory lesions. Non-inflammatory acne lesions include blackheads (open comedones) and whiteheads (closed comedones). Open and closed comedones along with papules and pustules are referred to as papulopustular acne, a form of inflammatory acne. The more severe the disease is, it involves more infected, inflammatory lesions. Nodular acne is the most severe form of inflammatory acne. If improperly treated, inflammatory acne lesions can produce deep scarring.